P1389: A NOVEL AND SUCCESSFUL CD7-TARGETED CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELL THERAPY FOR REFRACTORY/RELAPSED MIXED PHENOTYPE ACUTE LEUKEMIA (MPAL)
Authors: Xian Zhang, Junfang Yang, Jingjing LI, Liyuan Qiu, Peihua Lu
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia with features of both acute lymphoblastic leukemia and acute myeloid leukemia. The blast cells of MPAL may have a shared B/T/myeloid phenotype. Once relapsed, the prognosis is extremely poor for MPAL. Aims: We report the safety and efficacy of CD7 CAR-T therapy in treating refractory/relapsed (r/r) MPAL patients with CD7-positive in phase I clinical study (https://clinicaltrials.gov NCT04938115). Methods: Peripheral blood (PB) mononuclear cells were obtained from 10 patients or 1 patient transplant donor who relapsed post-transplant. T-cells were purified using CD3+ magnetic beads or CD4+ and CD8+ magnetic beads. The second-generation CD7 CAR with a 4-1BB costimulatory domain was manufactured according to the manufacturer’s protocol. Prior to the CAR-T cell infusion, patients received bridging chemotherapy to control rapid disease progression, and then all patients received conditioning regimens with intravenous fludarabine (30 mg/m2/d) and cyclophosphamide (300 mg/m2/d) (FC) lymphodepleting chemotherapy for three consecutive days (Day -5 to Day -3). The manufacturing time was 14 days. Results: From November 2020 to September 2022, 11 adult MPAL patients with CD7-positive expression ≥ 80% were enrolled. The median age was 28 years old (range: 18-45). A single dose of CD7 CAR-T cells was infused, 4 with a low dose (1-5 × 105/kg) and 7 with a medium dose (1.0 × 106/kg). The median transduction efficiency of the products was 84.4% (range: 32.0%-98.1%). Characteristics of enrolled patients are shown in Table 1. At enrollment, the median bone marrow (BM) blasts by morphology for the 8 patients with BM blasts were 15.0% (range: 0.5-79.5%), and 7 patients had extramedullary disease (EMD). Four patients had a prior allogeneic hematopoietic stem cell transplantation (allo-HSCT), including 1 who relapsed following a 2nd transplant and had also received CD19 CAR-T cell therapy before enrolling in this trial. On day 28, in BM, 10/11 (90.9%) patients achieved complete remission (CR) or CR with incomplete blood recovery, and all were minimal residual disease (MRD)-negative. Regarding the 7 patients with EMD, the overall response rate (ORR) was 5/7 (71.4%), including 4 CR and 1 partial response (PR), and 2 had no response (NR). The median follow-up time was 222 days (range: 60-791 days). Within 3 months post-CD7 CAR-T cell infusion, 7 patients both in MRD-negative CR and EMD CR received consolidative allo-HSCT, and all remained progression-free after a median follow-up of 561 days (range: 126-791 days), except for 2 who died from relapse and transplant-related mortality (TRM), respectively. For the other 4 patients less than CR, 1 died from progression disease, and 3 received salvage transplantation, of whom 2 died from TRM, and one was still alive at the last follow-up on day 278. The majority of patients developed mild cytokine release syndrome (CRS) (91% ≤ grade II), and only 1 had grade III CRS. None of the patients had neurotoxicity. Following infusion, the median peak of circulating CD7 CAR-T cells in PB was as high as 73.5% (25.8%~90.0%), occurring on day 14 (11-20) by flow cytometry. By qPCR, the median peak of CAR-T copy number was 2.58 ×105 (0.28-7.04 ×105) copies/µg DNA, which occurred on day 18(10-28). Summary/Conclusion: This study demonstrated that CD7-targeted CAR-T therapy was effective with a good safety profile in treating CD7-positive MPAL patients, even for those who relapsed post-transplant. However, more data on additional patients and longer observation time are needed.Keywords: CAR-T, T-ALL, T cell leukemia, Adult